Effects of Biguanides on Growth and Glycolysis of Bladder and Colon Cancer Cells.

Unlabelled: Background/ Aim: There is evidence that inhibitory effects of biguanides on oxidative phosphorylation require uptake of biguanides into the mitochondria. In this study the action of two biguanides that enter the mitochondria (buformin and phenformin) were compared with the action of two biguanides with poor uptake (phenyl biguanide and proguanil).

Materials And Methods: Effects on growth, glucose uptake and medium acidification were studied with two human colon cancer cells and seven bladder cancer cell lines.

Inhibition of Growth by Combined Treatment with Inhibitors of Lactate Dehydrogenase and either Phenformin or Inhibitors of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase 3.

Enhanced glycolysis in cancer cells presents a target for chemotherapy. Previous studies have indicated that proliferation of cancer cells can be inhibited by treatment with phenformin and with an inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB) namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). In the present work, the action of two inhibitors that are effective at lower concentrations than 3PO, namely 1-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP) and 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) were investigated.

Inhibition of Growth of Bladder Cancer Cells by 3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one in Combination with Other Compounds Affecting Glucose Metabolism.

In seven out of eight human bladder cell lines that were examined herein, growth was more dependent on the presence in the incubation medium of glucose rather than glutamine. The exception was the slowly growing RT4 cells that were more glutamine-dependent. Growth of all the cell lines was reduced by an inhibitor of 6-phosphofructo-2-kinase/2,6-bisphosphatase 3, namely 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO).

Growth inhibition of colon cancer cells by compounds affecting AMPK activity.

Aim: To determine if other molecules reported to modulate AMP-dependent protein kinase (AMPK) activity would have effects resembling those of metformin and phenformin on colon cancer cell proliferation and metabolism.

Methods: Studies were performed with four human colon cancer cell lines, Caco-2, HCT116, HT29 and SW1116. The compounds that were studied included A-769662, 5-aminoimidazole-4-carboxamide-1-ribofuranoside, butyrate, (-)-epigallocatechin gallate (EGCG), KU-55933, quercetin, resveratrol and salicylates.

Regulation of the proliferation of colon cancer cells by compounds that affect glycolysis, including 3-bromopyruvate, 2-deoxyglucose and biguanides.

In previous studies performed by our group, we observed that 2-deoxyglucose blocked the acidification of the medium used for culture of colon cancer cells caused by incubation with biguanides and it had an additive inhibitory effect on growth. In the present work, we found that 3-bromopyruvate can also prevent the lowering of pH caused by biguanide treatment. 3-Bromopyruvate inhibited colonic cancer cell proliferation, but the effect was not always additive to that of biguanides and an additive effect was more notable in combined treatment with 3-bromopyruvate and 2-deoxyglucose.

Addition of 2-deoxyglucose enhances growth inhibition but reverses acidification in colon cancer cells treated with phenformin.

A report that effects of butyrate on some cells may be mediated by activation of AMP-activated protein kinase (AMPK) prompted this study which examines if other AMPK activators can induce differentiation and inhibit proliferation of colon cancer cells in a manner similar to butyrate. Using induction of alkaline phosphatase as a marker, it was observed that compound C, an AMPK inhibitor, is able to reduce the differentiating effect of butyrate on SW1116 and Caco-2 colon cancer cells. Metformin was observed to be less effective than butyrate in the induction of alkaline phosphatase but was more effective as a growth inhibitor.

Inhibition of growth and induction of alkaline phosphatase in colon cancer cells by flavonols and flavonol glycosides.

We observed previously that quercetin can increase the activity of the differentiation markers alkaline phosphatase and dipeptidyl peptidase in Caco-2 colon cancer cells. In the present work, we compared the effects of quercetin on cell proliferation and differentiation with the action of related flavonols and quercetin glycosides. Relative to the action of quercetin, effects on growth and enzyme activities did not always follow parallel trends but quercetin 3-glucoside was notably more potent in both respects while quercetin rutinoside was less active.

Inhibition of growth and induction of differentiation markers by polyphenolic molecules and histone deacetylase inhibitors in colon cancer cells.

Previously we found that a fruit-derived polyphenol fraction caused an inhibition of proliferation and an induction of differentiation markers in Caco-2 human colon cancer cells. In the present work, we sought to determine if individual polyphenols would exert similar actions. Proliferation was inhibited by several polyphenolic molecules including gallic acid, ellagic acid, quercetin and resveratrol.

Inhibition of growth and induction of differentiation of colon cancer cells by peach and plum phenolic compounds.

The action of extracts from anthocyanin-enriched plums and peaches on growth and differentiation was studied with human colon cancer cells. Growth inhibitory effects were observed in Caco-2, SW1116, HT29 and NCM460 cells. In Caco-2 cells but not in the other cells studied there was evidence for increased differentiation as judged by increased activity of alkaline phosphatase and dipeptidyl peptidase.

Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists.

This study was initiated to determine if potential PPAR gamma antagonists could block the inhibition of cell proliferation caused by 4-phenylbutyrate. The action of 4-phenylbutyrate differed from other PPAR gamma ligands examined in that it induces histone acetylation. Proliferation of DS19 mouse erythroleukemia cells was inhibited by PPAR gamma agonists (4-phenylbutyrate, rosiglitazone, ciglitazone and GW1929) and by potential PPAR gamma antagonists: BADGE (Biphenol A diglycidyl ether), GW9662, PD068235 and diclofenac.

Induction of histone acetylation and inhibition of growth by phenyl alkanoic acids and structurally related molecules.

Purpose: A structure-activity study was undertaken to determine the influence of side chain length of phenyl alkanoic acids and the degree of unsaturation of phenyl alkenoic acids on the induction of histone acetylation and inhibition of cancer cell proliferation.

Materials And Methods: Studies on cell proliferation were performed with DS19 mouse erythroleukemic cells, PC-3 human prostate cancer cells and Caco-2 human colon cancer cells. Actions on histone deacetylase and the induction of histone acetylation were compared for 4-phenylbutyrate and structurally related molecules.

Induction of histone acetylation and inhibition of growth of mouse erythroleukemia cells by S-allylmercaptocysteine.

Growth-inhibitory effects on DS19 mouse erythroleukemia cells were seen in the micromolar concentration range with allicin and S-allylmercaptocysteine and in the millimolar range with allyl butyrate, allyl phenyl sulfone, and S-allyl cysteine. Increased acetylation of histones was induced by incubation of cells with the allyl compounds at concentrations similar to those that resulted in the inhibition of cell proliferation. The induction of histone acetylation by S-allylmercaptocysteine was also observed in Caco-2 human colon cancer cells and T47D human breast cancer cells.

Genistein alters methylation patterns in mice.

In this study we examine the effect of the phytoestrogen genistein on DNA methylation. DNA methylation is thought to inhibit transcription of genes by regulating alterations in chromatin structure. Estrogenic compounds have been reported to regulate DNA methylation in a small number of studies.